CN1144584C - 缓释组合物及其制备方法 - Google Patents
缓释组合物及其制备方法 Download PDFInfo
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- CN1144584C CN1144584C CNB988052202A CN98805220A CN1144584C CN 1144584 C CN1144584 C CN 1144584C CN B988052202 A CNB988052202 A CN B988052202A CN 98805220 A CN98805220 A CN 98805220A CN 1144584 C CN1144584 C CN 1144584C
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
本发明涉及微囊或植入物形式的组合物，该组合物含有可生物降解聚合物或共聚物型赋形剂或此类赋形剂的混合物以及活性物质或活性物质的混合物，所述赋形剂或赋形剂的混合物在氯仿中具有0.5dl/g-1.6dl/g的特性粘度。所述微囊或所述植入物能够在长达3个月或更长的延迟时间内释放出活性物质或活性物质混合物。所述组合物还含有高比表面的活性成分。
Description
本发明首先涉及一种呈含有可生物降解聚合物或共聚物型赋形剂或此类赋形剂混合物以及至少一种活性物质的微囊或植入物形式的组合物，所述赋形剂或赋形剂混合物在氯仿中具有0.5dl/g至1.6dl/g的特性粘度。本发明还涉及一种呈含有至少一种高分子量的可生物降解聚合物或共聚物以及至少一种具有高比表面的水溶性活性物质的微囊或植入物形式的组合物。所述组合物被用于在长达三个月以上的延迟时间内持续释放活性物质。
上述组合物，特别是微囊，主要用于药剂学领域，但是也适用于其他领域，尤其是农业化学，即植物保护的领域。
不论是常规药物产品如甾类、肽类或蛋白质类(参加如Boswell的美国专利US 3,773,919)，抑或是用于植物保护的产品，将这些活性成分以缓释组合物形式施用早已被公认为颇具价值。所述剂型可以采用其中活性成分与可生物降解聚合物或共聚物如聚丙交酯/共聚乙交酯共聚物(PLGA)混合的微粒形式。
业已发现，特别是在寻求一种更恒定的在任何情况下均不间断的释放模式时，需要较低分子量，即低粘度的PLGA型聚合物，这种模式是指例如在欧洲专利EP 58 481中称作“单相”的释放模式。就此可提及欧洲专利EP 21 234、EP 52 510和EP26 599；其中EP 21234可参见其实施例8.B.2中公开的特性粘度为0.5dl/g的聚合物，EP 52 510中对粘度为0.38dl/g的处于六氟异丙醇(HFIP)中的共聚物进行了体内试验，和EP26 599公开了例如粘度为0.12-0.20dl/g的聚合物并且要求保护粘度为0.08-0.30dl/g的聚合物。上述专利述及的聚合物被用作能够产生恒速释药的组合物。例如，专利EP26599中含有节育药。
在此方面同样值得注意的是，于本专利申请的申请日，欧洲专利58 481正处于异议程序之中，申请人已将其主权利要求限定于唯一能够产生单相型释放的低粘度(低于0.3或0.5dl/g)聚合物。
此外，当需要更长期(如一个月以上)释药时，会出现更复杂的问题，例如专利EP0 302 582中提供了一种解决方案，其中包括将由粘度不同的聚合物构成的微囊混合在一起。
近期，本申请人发现某些高粘度聚合物适合于制备长效缓释组合物。并且还发现，利用某些聚合物可以生产具有长时间单相释放性能而且不存在无释放的起始阶段(静止期)的组合物。具体所采用的聚合物在氯仿中的特性粘度适宜至少为0.5dl/g，并且更优选至少为0.6或0.7dl/g。但总之，这些聚合物在氯仿中的特性粘度应不超过1.6dl/g，并且可以低于1.4或1.2dl/g。所述聚合物优选为其丙交酯/乙交酯配比在40/60-90/10，优选约为75/25的PLGA类物质。
本发明的聚合物可以通过常规方式制备，具体可通过打开丙交酯或乙交酯的环系来制备。在诸如美国专利US3,773,919中公开了此类开环方法。
在本发明中，还可以采用具有不同较高粘度的聚合物的混合物，但优选的组合物中只含有一种聚合物或共聚物。
所以，本发明首先涉及一种微囊或植入物形式的组合物，该组合物含有可生物降解的、在氯仿中的特性粘度为0.5dl/g-1.6dl/g的聚合物或共聚物型赋形剂或此类赋形剂混合物以及一种活性物质或活性物质混合物，这些微囊或植入物可以在至少为1个月，优选至少2个月，更优选至少为3个月的长时间内释放出活性物质或活性物质的混合物。
还应将所述微囊理解为包括微球、微粒、毫微囊、毫微球或毫微粒。所述聚合物的含义应为聚合物、共聚物或这些个体的任意混合物。最后，应将所述活性物质的含义理解为活性物质、其一种盐、其一种前体或上述化合物的任意混合物。
适用于本发明组合物的活性物质的盐可具体包括：由有机酸形成的盐，如乙酸盐、苹果酸、酒石酸盐、草酸盐、富马酸盐、柠檬酸盐、乳酸盐、硬脂酸盐、扑酸盐(1，1’-亚甲基-二(2-羟基-3-萘甲酸)盐)、甲磺酸盐或对-甲苯磺酸盐；由无机酸形成的盐，如盐酸盐、硫酸盐、磷酸盐或氢溴酸盐。优选采用通过与例如乙酸以阳离子形式发生成盐作用获得的水溶性产物。但是，也可以采用不溶性盐，例如(1，1’-亚甲基-二(2-羟基-3-萘甲酸)盐)。
本发明具体涉及一种含有可生物降解聚合物或共聚物型赋形剂或此类赋形剂的混合物以及活性物质或活性物质混合物的呈微囊或植入物形式的组合物，所述微囊或植入物能够在长达3个月或更长的时间内以基本单相的释放模式释放活性物质或其混合物，所述组合物的特征在于：
-当组合物为微囊形式时：
·所述聚合物或共聚物在氯仿中的粘度介于0.7dl/g-1.6dl/g之间，并且该微囊的制备过程中不包括所述微囊的溶化阶段，
·或所述聚合物或共聚物在氯仿中的粘度介于0.5dl/g-1.6dl/g，并且所述聚合物或共聚物具有亲水特性；
-当所述组合物为植入物形式时，所述聚合物或共聚物在氯仿中的粘度为0.5dl/g-1.6dl/g。
适用于本发明组合物的聚合物或共聚物在氯仿中的粘度优选至少等于0.9dl/g。
特别适用于本发明的聚合物或共聚物尤其可以是聚合物如乳酸、乙醇酸、柠檬酸或苹果酸的聚合物，或是其它可生物降解聚合物如聚-β-羟基丁酸、聚原酸酯、聚原碳酸酯、聚-α-氰基丙烯酸酯、聚草酸链烷二醇酯如聚草酸丙二醇酯或丁二醇酯、聚氨基酸等。也可以采用共聚物，如PLGA、聚苯乙烯、聚甲基丙烯酸、甲基丙烯酸/丙烯酸共聚物、聚氨基酸、马来酸酐共聚物、乙基纤维素、硝基纤维素、乙酰基纤维素等。这些聚合物或共聚物可以单独使用也可混合采用。通常，PLGA含有40-90％丙交酯以及10-60％乙交酯。优选采用D，L-PLGA，并且更优选采用由70-80％DL-丙交酯和20-30％乙交酯制成的D，L-PLGA。特别适用于本发明的是由75％DL-丙交酯和25％乙交酯合成的PLGA。
另一种特别适用于本发明的聚合物是由L-丙交酯和乙交酯制成的L-PLGA。与具有相同粘度的D，L-PLGA相比，L-PLGA释放速度更缓慢并且可以被用作粘度更高的D，L-PLGA的替代物。
从常规方式来说，适宜采用具有亲水特性的聚合物或共聚物。所以，一般优选由疏水性起始物如十二烷醇开环制得的PLGA和由亲水性起始物如乳酸或乙醇酸开环得到的PLGA。
亲水性聚合物或共聚物，是指其中端链具备极性(例如端链的末端是酸性官能团)的聚合物或共聚物，这与具有非极性端链(例如端链为脂肪链)的疏水性聚合物或共聚物相反。
酸值对于聚合物或共聚物的亲水性或疏水性来说似乎是最相关的参数，所谓酸值是对1克聚合物中和游离酸度所需的氢氧化钾毫当量数。由于聚合物或共聚物的端链可以带有游离酸官能团，所以，可以依据单体特性测定酸值。
本申请人发现，通常情况中，亲水性聚合物产生一种较好的缓释曲线。所以，适用于本发明的聚合物的酸值优选至少等于1，更好地至少等于1.2，并且更优选至少等于1.5或2。
本发明所述微囊的活性物质含量，即内部负荷，即微囊内纯净肽的重量相对于微囊总重量的比例通常为0-20％，优选为2-15％。对于曲普瑞林乙酸盐，其可释药约3个月的剂型的负荷优选小于或等于10％，并且更优选4-8％。对于兰瑞肽乙酸盐，其负荷优选为10-20％。
在植入物中，活性物质负荷一般为0-30％，并且适宜为15-25％。
包封步骤可以称作凝集，如美国专利US3 773 919或欧洲专利EP52 510所述。
也可以采用所谓的熔融-挤出法，如欧洲专利EP58 481或美国专利US5 225 205所述，随后视具体情况而定以常规方法研磨所得产物得到微粒。
另一方面，可以采用水溶性活性成分，例如肽的水溶性盐(如乙酸盐)。也可以采用可溶性化合物的不溶性盐，例如肽的脂肪酸盐(如肽的扑酸盐)，如同在例如英国专利GB2 209 937中所述的。
利用本发明所述聚合物、经熔融-挤出法制成的组合物也可以以植入物形式提供并且可被直接投入使用。
适宜采用直径约为1mm，例如0.8-1.2mm的小植入物(小型植入物或微型植入物)。这些植入物的长度可在例如10-35mm之间，如约25mm。含有低剂量活性成分例如每个植入物含有约3mg曲普瑞林乙酸盐的植入物产生非常好的结果。此类植入物可以在长达3个月或更长的时间内释放活性成分。
此外，我们发现，活性成分的构型也会对产品的扩散产生影响。特别是如果活性成分可以结晶或无定形形式得到时，不能随意地对两种形式进行选择。
专利申请EP709 085中描述了含有聚合物和无定形水溶性活性物质的微囊。其中具体阐述了获得小颗粒(优选粒度小于10m)活性物质的重要性。但是，该专利申请没有公开任何制备这种颗粒的方法，并且未提及活性成分颗粒的比表面对含有这些颗粒的组合物的释放性能所产生的影响。如今，本申请人业已从1986年始采用含有无定形活性物质的微囊，也就是采用含有3.75mg以Decapeptyl商品名销售的曲普瑞林乙酸盐的微囊，其粒度只有约8μm。然而，迄今发现，粒度不是唯一的有利于缓释药物长达3个月以上时间的决定性参数。
原则上说，对于例如肽类或蛋白质类的产品而言无定形特征并不会产生问题，这些产品的制备方法，特别是冷冻干燥法在多数情况中产生的是无定形产物，例如Decapeptyl 3.75mg。
在文献中已对这种现象作了大量描述，并且特别值得提及的是下列文章：Hsu，C.C.等人，《药物研究》，12(1)，68-77(1995)或Towns，J.K.《色谱学杂志》，A，705(1)，115-27(1995)。
所以，本发明还涉及一种微囊或植入物形式的组合物，该组合物含有至少一种优选为高分子量的可生物降解聚合物或共聚物以及至少一种高比表面的水溶性活性物质。具体来说，所述比表面大于2m2/g，并且优选大于3m2/g。更优选所述比表面大于5m2/g或10m2/g。特别优选所述比表面大于20m2/g，首选大于30m2/g。
本发明优选地涉及其中水溶性活性物质是蛋白质或肽的上述组合物。
本发明还涉及其中聚合物或共聚物在氯仿中的粘度为0.5-1.6dl/g，优选0.9-1.6dl/g的上述组合物。尤其是应选用粘度为0.7-1.3dl/g的聚合物或共聚物，并且更优选粘度为0.9-1.3dl/g的聚合物或共聚物。尤其适用的聚合物是PLGA。所述PLGA适宜由40-90％丙交酯和10-60％乙交酯，更优选含有70-80％丙交酯和20-30％乙交酯制备。掺混在所速微囊或植入物中的水溶性活性物质优选是蛋白质类或肽类。
在优选的含有高比表面活性物质的组合物中，聚合物或共聚物在氯仿中的粘度在0.5-1.6dl/g之间，并且所述聚合物或共聚物具有亲水特性，聚合物或共聚物的酸值大于1毫当量(meq)KOH/克聚合物或共聚物，优选大于1.2meq，更优选1.5meq或2meq KOH/克聚合物或共聚物。
本发明还涉及含有高比表面活性物质的微囊或植入物形式的组合物，其特征在于所述聚合物或共聚物为PLGA，优选由70-80％丙交酯和20-30％乙交酯制成的PLGA，所述PGA在氯仿中的粘度为0.5-1.6dl/g，并且混在微囊或植入物内的活性物质为蛋白质或肽。
与某些采用低分子量聚合物的其它制剂相比，这些微囊或植入物能够呈现出一个单相释放曲线，其中的起始峰(或突起)降低，由此使这些微囊或植入物能够在长达3个月或更长的时间内释放活性物质。
换言之，本申请人发现，对于微囊或植入物形式的组合物，具体如基于PLGA和包括肽或蛋白质作为活性成分的组合物来说，其释放性质，特别是单相型释放作用可以在至少下列特性之一存在的条件下得到显著改进：
a)所述聚合物或共聚物是PLGA，其在氯仿中的粘度高于0.5dl/g，优选高于0.9dl/g且原则上低于1.6dl/g；
b)所述聚合物或共聚物是由70-80％丙交酯和20-30％乙交酯制成的PLGA；
c)所述聚合物或共聚物具有亲水特性，并且其酸值优选地大于1meqKOH，更优选大于1.2或1.5meq KOH/克聚合物或共聚物；
d)所述活性成分，优选是肽或蛋白质，具有高比表面并且大于2m2/g，优选大于10m2/g，更优选大于20m2/g或30m2/g。
这些特征可以视具体情况而定与L-PLGA而不是与D，L-PLGA的使用相结合。
根据申请人所了解到的实际情况，申请人估计特性d)自身非常重要并且可以有利地与其它特性a)、b)或c)相结合。具体地，特性d)可以与下列特性相结合：单独a)、单独b)、单独c)、a)+b)、a)+c)、b)+c)或a)+b)+c)。更优选地，使特性d)与至少特性c)相结合。
在适合本发明不同需要的活性物质中，特别值得提及的是蛋白质类和肽类。所述活性物质可选自：曲普瑞林或其盐，具体如曲普瑞林乙酸盐；兰瑞肽或其一种盐，具体如兰瑞肽乙酸盐；奥曲肽或其一种盐(如欧洲专利EP29 579所述)，具体如奥曲肽乙酸盐或扑酸盐；具有LH-RH活性的化合物，如曲普瑞林、戈舍瑞林、亮丙瑞林、布舍瑞林或其盐；LH-RH拮抗剂；GPIIb/IIa拮抗剂；具有与GPIIb/IIa拮抗剂相似活性的化合物；促红细胞生成素(EPO)或其类似物；不同类型的干扰素-α、干扰素-β或-γ；生长激素释放抑制因子；生长激素释放抑制因子衍生物(如欧洲专利EP 215 171中公开的)；生长激素释放抑制因子类似物(如美国专利US5 552 520中公开的，该专利中还包括了其它公开了生长激素释放抑制因子类似物的专利的目录，这些文献均引入本申请作为参考)；胰岛素；生长激素；生长激素释放因子(GRF)；生长激素释放肽(GHRP)；表皮生长因子(EGF)；促黑素细胞素(MSH)；促甲状腺素释放激素(TRH)或其盐或其衍生物；甲状腺刺激激素(TSH)；促黄体素(LH)；促滤泡素(FSH)；甲状旁腺素(PTH)或其衍生物；溶菌酶盐酸盐；甲状旁腺素相关肽(PTHrp)；和人体PTH激素的N-末端肽片段(1→34位)；后叶加压素或其衍生物；催产素；降钙素；与降钙素具有相似活性的降钙素衍生物；降钙素基因相关肽(CGRP)；高血糖素；高血糖素相似肽(GLP)；胃泌素；胃泌素释放肽(GRP)；肠促胰液肽；促胰酶素；缩胆囊素；血管紧张素；人胎盘催乳激素；人绒毛膜促性激素(HCG)；脑啡肽；脑啡肽衍生物；集落刺激因子(CSF)；内啡肽；京都酚；白介素类，例如白介素-2；吞噬细胞激素；胸腺生成素；胸腺刺激素；胸腺激素因子(THF)；胸腺血清因子(TSF)；胸腺血清因子(TSF)衍生物；胸腺素；胸腺因子X；肿瘤坏死因子(TNF)；胃动素；铃蟾肽或其衍生物(如美国专利US5 552520所述，该专利还包括了其它公开了铃蟾肽衍生物的专利的目录，这些文献均引入本申请作为参考)；催乳激素；神经降压素；强啡肽；雨蛙肽；P物质；尿激酶；天冬酰胺酶；缓激肽；激肽释放酶；神经生长因子；凝血因子；多粘菌素B；多粘菌素E；短杆菌肽；杆菌肽；蛋白质合成刺激肽；内皮素拮抗剂或其盐或其衍生物；血管活性肠肽(VIP)；促肾上腺皮质激素(ACTH)或其片段；血小板衍生生长因子(PDGF)；骨形态发生蛋白(BMP)；垂体腺苷酸环化酶活化多肽(PACAP)；神经肽Y(NPY)；肽YY(PYY)；肠抑胃肽(GIP)；和多核苷酸，具体如双链RNA(ds-RNA)，如专利申请EP0300680或法国专利2622 586所述。
优选地，将ds-RNA理解为与聚尿苷酸复合的聚腺苷酸，也称作聚(A)-聚(U)或聚腺苷尿苷酸(poly-adenur)。其它RNA也适用于本发明，具体如聚肌苷酸与聚胞苷酸的复合物，其也可称作聚(I)-聚(C)，以及通过在这种聚胞苷酸链中引入尿苷酸获得的改性复合物，例如由HEMISPHERx公司提供的产品扩增基因(Ampligen)(这些产品具体公开在欧洲专利申请EP0 300 680中)。ds-RNA优选地通过法国专利2 622 586中所述方法制备。
当上述活性物质为水溶性物质或被转化为水溶性物质时，就可以获得高比表面，所述转化方式可例如是成盐作用或在结构中引入水溶性链。这对于上述肽类和蛋白质类物质来说特别有效。在本发明这方面来说，所属领域技术人员可以采用其它任何认为适当的水溶性活性物质或其盐或其前体，特别是与乙酸成盐制得的盐。
根据本发明的一个优选方面，具有高比表面的肽或蛋白质选自曲普瑞林乙酸盐、兰瑞肽乙酸盐或奥曲肽乙酸盐。
在本申请中应将肽和/或蛋白质理解为肽和/或蛋白质本身以及这些肽类或蛋白质类的药理活性片段、盐或衍生物。
用于制造本发明所述微囊或植入物的水溶性活性物质，具体如曲普瑞林乙酸盐、兰瑞肽乙酸盐和奥曲肽乙酸盐、戈舍瑞林、亮丙瑞林、布舍瑞林或其盐优选通过一种主要包括两个步骤的方法获得：
-冷冻干燥步骤，其中包括将水溶性物质的稀溶液快速浸渍在温度低于-50℃，优选低于-70℃的介质内；和
-视具体情况而进行的研磨步骤，其中优选地包括超声研磨。
应将活性物质的稀溶液理解为所述活性物质的浓度小于其饱和浓度的一半并且优选小于其饱和浓度的四分至一的溶液，条件是其饱和浓度至少等于200g/l。此方法制备出高比表面的活性物质。
快速浸渍应被理解为与低温介质相接触，从而引起水溶性物质的溶液瞬时冻结。
对于冷冻干燥而言，在进行实际冻干前，该溶液可以在例如处于液氮罐中的浮盘内冷冻。
为了获得最大比表面，对溶液的快速浸渍优选地历经将活性物质溶液微粉化的过程。当首先将活性物质溶液微粉化时，低温介质的温度可以只低于-50℃。
例如，为了获得极高的比表面，可以选择将溶液通过喷雾器喷雾到极低温的金属盘上。金属盘的温度优选地低于-50℃，更优选低于-70℃，甚至-80℃或-120℃。例如通过将金属盘浸渍在极低温介质如液氮中可以获得这样的温度。按照本发明的一个优选方案，所述金属盘为凹形并且利用喷雾器将溶液喷雾到该盘内。
也可以考虑采用其它冷冻技术，例如将活性物质的溶液喷雾到该活性物质的预冷非溶剂浴中。所述非溶剂优选是液化气体，例如液氮。
另一种可能的作法是在转鼓式致冷机上冷冻活性物质溶液。如上所述，在进行该冷冻过程之前，优选对活性物质溶液进行微粉化处理。
当为了制备本发明所述缓释微囊或植入物而采用在盘中冷冻活性物质的方法时，优选活性物质的比表面在冷冻干燥后和研磨前大于2m2/g。更优选地，活性物质的比表面大于3m2/g，甚至大于5m2/g。
若需要使比表面大于10m2/g，则优选采用包括微粉化步骤的方法。活性物质在冷冻干燥后获得的比表面优选大于15m2/g。此比表面更优选大于20m2/g甚至大于30m2/g。
为了得到不同的比表面，可通过改变参数例如冷冻速度或溶液浓度使活性物质溶液的冷冻条件发生变化。
活性物质的比表面是获得长时间缓释的有利因素，对于微囊来说尤其如此。事实上已提出，粒度相同但比表面不同的活性物质颗粒对于相同的高分子赋形剂来说将产生完全不同的结果。
所以，本发明还涉及适用于水溶性生物活性物质的上述制备方法以及由此方法获得的具有高比表面的水溶性生物活性物质。
具体来说，本发明涉及由上述方法制得的曲普瑞林乙酸盐、兰瑞肽乙酸盐或奥曲肽乙酸盐，或双链RNA，优选地由此类方法制得的聚腺苷酸复合聚尿苷酸。
如上指出，本发明组合物优选被用于制药领域。所述药物组合物可以通过不同途径施用给病患，但是，优选经皮下或肌肉内给药。可将本发明所述微囊首先悬浮在适于注射的载体中，例如氯化钠水溶液或甘露糖醇水溶液。
除非另有定义，本文所用的全部科技术语具有本发明所属技术领域的常用含义。另外，在此提及的所有出版物、专利申请、专利以及其它参考文献引入本申请作为参考。
下列实施例用于说明上述方法，但不可理解为对本发明范围构成限定。
实施例
对于这些实施例，特性粘度(IV)是通过常规的流动时间测定法，例如《欧洲药典》，1997，17-18页(毛细管测定法)测出；除非另有说明，这些粘度均在在氯仿中和25℃下以0.1％的浓度测定，或于30℃下在六氟异丙醇中以0.5％的浓度测定。在测定中，活性物质的比表面是通过所谓的BET法(对活性物质表面上氮单层的吸收)测定，这是一种本领域技术人员熟知的方法。
对于下列实施例，按照本发明所述冷冻干燥过程得到的肽称作“改性”肽，与“未改性”肽相对照，“未改性”肽是以常规方法进行冻干(未经过猝发式低温浸渍)
实施例1
将16.620g“未改性”曲普瑞林乙酸盐溶解在554ml水中。将溶液在置于液氮罐中的浮盘内冷冻，随后冻干。
由此得到15.18g“改性”曲普瑞林乙酸盐，收率为91.34％。此化合物具有4.7m2/g的比表面，冷冻干燥前的比表面为0.8m2/g。
随后，将曲普瑞林乙酸盐超声粉碎：对于改性肽来说15分钟就足以获得粒度小于10μm的颗粒(对于未改性肽来说需要30分钟才能够获得如此的粒度)。
随后按照欧洲专利EP52 510和美国专利US 3 773 919中所述的凝聚方法进行包封步骤，以3.378g上述碎化的改性曲普瑞林乙酸盐和D，L-PLGA(D，L-PLGA由75％DL-丙交酯和25％乙交酯组成，在氯仿中的特性粘度＝0.70dl/g，酸值＝1.61meq KOH/g)的7.30％二氯甲烷溶液为起始物。加入390ml硅油以便通过凝聚作用形成微囊。浸渍在庚烷浴(22L)中并且在10μm的膜上过滤后回收所述微囊。
实施例2
将超声碎化30分钟后粒度为8μm的0.338g未改性曲普瑞林乙酸盐在搅拌条件下加入到D，L-PLGA(PLGA与实施例1中的PLGA等量)的7.30％二氯甲烷溶液中。加入40ml硅油以形成微囊，随后在庚烷浴(2L)中沉淀并且再在10μm的膜上过滤。
实施例3-6
将0.338g曲普瑞林乙酸盐按照上面表1中所述的条件改性，随后超声碎化，再将其加入到溶于二氯甲烷中的三种D，L-PLGA(其特性如下表2所示)的33.3％/33.3％/33.3％混合物的7.30％溶液中。加入40ml硅油以形成微囊，随后在庚烷浴(2L)中沉淀并且再在10μm的膜上过滤。
表1
| 实施例 | 浓度(g/l) | 曲普瑞林乙酸盐含量(g) | 水的用量(ml) | 比表面(m2/g) |
| 3456 | 20015010050 | 3333 | 15203060 | 4.44.74.87.3 |
(未改性)曲普瑞林乙酸盐丁酸起始物的比表面为0.8m2/g。
三种混合聚合物的物理化学特性列于表2中：
| 特性 | 第一种PLGA | 第二种PLGA | 第三种PLGA |
| 丙交酯/乙交酯比例氯仿中特性粘度(dl/g)酸值(meq KOH/g) | D，L-PLGA50∶500.472.68 | D，L-PLGA75∶250.612.08 | D，L-PLGA75∶250.701.61 |
实施例7
将22.560g“未改性”兰瑞肽乙酸盐溶解在752ml水中。将该溶液在置于液氮罐中的浮盘内冷冻，随后冻干。得到21.75g“改性”兰瑞肽乙酸盐，收率为96.41％，此化合物具有4.4m2/g的比表面。
随后按照欧洲专利EP52 510和美国专利3 773 919中所述的凝聚法进行包封步骤，以7.5g上述碎化的改性兰瑞肽乙酸盐和D，L-PLGA(D，L-PLGA由50％DL-丙交酯和50％乙交酯组成，在HFIP中的特性粘度＝0.55dl/g)的3.70％二氯甲烷溶液为起始物。加入650ml硅油以便通过凝聚作用形成微囊。浸渍在庚烷浴(30L)中并且在10μm的膜上过滤后回收所述微囊。
实施例8和9
用不同重均分子量(Mw)的D，L-PLGA(由75％DL-丙交酯和25％乙交酯组成)来制造曲普瑞林乙酸盐的微囊。采用比表面为4.7m2/g的曲普瑞林乙酸盐、按照实施例1所述方法制备微囊。
实施例8和9的物理化学参数如下表所示：
| 实施例 | Mw THF | IV CHCl3(dl/g) | 酸值(meq KOH/g) |
| 89 | 58,400132,650 | 0.610.93 | 2.081.31 |
实施例10：
按照实施例1所述的方法、采用具有疏水趋势的D，L-PLGA(该D，L-PLGA由75％DL-丙交酯和25％乙交酯组成；在THF中测得的分子量：80100；在氯仿中的特性粘度：0.75dl/g；酸值＝0.40meq KOH/g)制备微囊。
实施例11：
按照实施例1所述的方法、采用有结晶趋势的L-PLGA(该L-PLGA由75％L-丙交酯和25％乙交酯组成；在THF中测得的分子量：99260；在氯仿中的特性粘度：0.78dl/g；酸值＝1.80meq KOH/g)为起始物制备微囊。
实施例12：
将1重量份的曲普瑞林乙酸盐加入到4重量份的粉化D，L-PLGA(该PLGA由75％丙交酯和25％乙交酯组成；在THF中测得的分子量：103810；在氯仿中的特性粘度：0.82dl/g)中。
用400μm筛将固体块破碎，将产物以42rpm的转速混合20分钟并且将该混合物在120℃下用一个位于螺旋挤压机上的直径为1mm的挤压模挤出。随后将挤出物在空气中冷却并且通过拉丝使其最终的直径达到0.85mm。
测定每单位长度(mm)的混合物浓度，并且将挤出物棒切成预定长度(在此为24mm)，得到含有3mg曲普瑞林的微型植入物。最后，检测各微型植入物的重量。
实施例13和14
这两个实施例采用同样的方法：
5g兰瑞肽乙酸盐溶解在水中以达到所选择的浓度(例如，加入167ml灭菌水，所得浓度为30g/l)。用500ml的喷雾器将这种溶液雾化，调节喷雾流得到尽可能细的液滴。将所得液滴喷雾在底部浸渍在液氮中的盘中。在操作前在盘内放置两根温度计，以便监测产物的温度变化。
一旦产物被冻结，将盘插入到底盘温度约为-54℃的冷冻干燥器中。
用1小时使产物温度和底盘温度达到平衡。这可以诱发升华阶段(将底盘温度设定在20℃并且罐内压力为100μbar)。此阶段持续约30小时。产物的平均最终温度为13℃。随后进行约24小时的二次干燥(罐内压力50μbar)。产物的平均最终温度是20℃。
所用反应物和产物的特性概括在下表中：
| 特性 | 实施例13 | 实施例14 |
| 兰瑞肽乙酸盐的用量(g) | 5.00 | 5.00 |
| 溶液浓度(g/l) | 30 | 10 |
| 兰瑞肽乙酸盐的回收量(g) | 4.54 | 4.10 |
| 所得比表面(m2/g) | 36 | 43 |
将上述(实施例14)得到的比表面为43m2/g的兰瑞肽乙酸盐按照下列方法混合到微囊内：
在玻璃管中称量0.782g兰瑞肽乙酸盐。将15ml二氯甲烷加入到该肽盐中。用装备有放大器和浸插探针或平头探针的超声发生器将上述肽超声粉碎(频率＝50Hz，功率＝250W；粉碎持续约15分钟)。
随后按照欧洲专利EP52 510和美国专利3 773 919中所述的凝聚法使用0.782g上述碎化的兰瑞肽乙酸盐和溶于35ml二氯甲烷中的4g 50∶50D，L-PLGA(在氯仿中的IV＝0.48dl/g)溶液进行包封步骤。加入34.2ml硅油以便通过凝聚作用形成微囊。浸渍在庚烷浴(2.5L)中并且在10μm的膜上过滤后回收所述微囊。
随后将所得的微球真空干燥，分装到瓶中并且与赋形剂(例如惰性物质或表面活性剂)一起冷冻干燥，以确保储存在良好的条件下并且易于得到微囊的悬浮液。
实施例15和16：
这两个实施例采用与实施例1相似的方法。所用的肽也相同。但所用PLGA的特征、肽(此两个实施例采用改性曲普瑞林乙酸盐)的用量以及微囊的制备参数如下表所示：
| 特性 | 实施例15 | 实施例16 |
| 改性曲普瑞林乙酸盐的用量(g) | 2.58 | 2.58 |
| 聚合物用量(g) | 30 | 30 |
| 硅油用量(ml) | 600 | 650 |
| 二氯甲烷用量(ml) | 812 | 812 |
| 丙交酯/乙交酯比例 | 75/25 | 75/25 |
| PLGA在氯仿中的粘度(dl/g) | 0.96 | 0.96 |
| 测定的酸值 | 1.22 | 1.12 |
对本发明微囊的释放曲线的研究
为了说明本发明微囊的价值，对其体外释放曲线作了研究：
将实施例1-11和15-16各取3个约25mg(实施例7取约20mg)的微囊样品置于4ml 0.9％氯化钠溶液中，分别测定其释放性能。在37℃下，在1小时、1天和4天后提取释放到溶液中的药物。
利用高效液体色谱(HPLC)、相对于校准范围、在三氟乙酸(TFA)体系中以梯度模式测定曲普瑞林。为了得到曲普瑞林的标准范围，按照下列方法制备溶液T1：将约7.5mg参比曲普瑞林乙酸盐样品置于50ml烧瓶中；用0.1％乙酸溶液配制到50ml。由溶液T1制备溶液T2和T3：对于T2，取10ml溶液T1并且用0.1％乙酸溶液配制到20ml。对于溶液T3，取1ml溶液T1并且用0.1％乙酸溶液配制到50ml。
按照类似的方法通过HPLC测定兰瑞肽。为了得到兰瑞肽的校准范围，按照下列方法制备溶液T’1：将约16.5mg参比兰瑞肽乙酸盐样品置于50ml烧瓶中；用0.1％乙酸溶液配制到50ml。由溶液T’1制备溶液T’2、T’3、T’4和T’5：对于T’2，取10ml溶液T’1并且用0.1％乙酸溶液配制到25ml。对于溶液T’3，取5ml溶液T’1并且用0.1％乙酸溶液配制到25ml。T’4通过将2ml溶液T’1用0.1％乙酸溶液稀释到总体积为25ml制得。溶液T’5通过将1ml溶液T’1用0.1％乙酸溶液稀释到总体积为25ml制得。
以相对于曲普瑞林乙酸盐或兰瑞肽乙酸盐的起始含量的百分比(100％)计，测定曲普瑞林乙酸盐或兰瑞肽乙酸盐的量，这可作为参比。
该体外试验的结果概括在下表中：
| 实施例 | 释放的总量(％) | ||
| 1小时 | 1天 | 4天 | |
| 1 | 8 | 16 | 27 |
| 2 | 9 | 47 | 57 |
| 3 | 10 | 45 | 67 |
| 4 | 10 | 37 | 65 |
| 5 | 9 | 41 | 66 |
| 6 | 8 | 30 | 55 |
| 7 | 3 | 14.5 | 28.3 |
| 8 | 11 | 40 | 67 |
| 9 | 2 | 4 | 6 |
| 10 | 5 | 12 | 14 |
| 11 | 1 | 2 | 2 |
| 15 | 2 | 4 | 13 |
| 16 | 2 | 5 | 10 |
体内试验的结果与那些体外试验完全相关。例如，将实施例1的微囊以1.2mg/kg的剂量肌内注射到大鼠体内。对血浆的分析揭示了曲普瑞林的量在超过90天的期间内恒定地保持在0.1ng/ml以上。对实施例2的微囊进行的相同研究显示出睾酮的量在超过90天的期间内恒定地保持在1ng/ml以下。此外，将实施例9的微囊以1.2mg/kg的剂量肌内注射到大鼠体内，对血浆的分析揭示了曲普瑞林的量在超过90天的期间内恒定地保持在0.1ng/ml以上。
按照下列方法对实施例12的微型植入物进行体内试验：在每只短腿小猎兔犬(体重约12kg)的后爪肌肉内注射总剂量为3mg的曲普瑞林。血浆分析揭示出，曲普瑞林的量在超过90天的期间内恒定地保持在0.1ng/ml以上。
Claims (8)
1.呈微囊或植入物形式的组合物，其中含有丙交酯和乙交酯的共聚物或此类共聚物的混合物以及蛋白或肽，所述共聚物或共聚物混合物在氯仿中的粘度为0.5～1.6dl/g，并且其酸值大于1meq KOH/克共聚物。
2.权利要求1的呈微囊或植入物形式的组合物，其特征在于所述丙交酯和乙交酯的共聚物在氯仿中具有至少等于0.9dl/g的特性粘度。
3.权利要求1的组合物，其特征在于所述共聚物的酸值大于1.2meqKOH/克共聚物。
4.权利要求3的组合物，其特征在于所述共聚物的酸值大于1.5meqKOH/克共聚物。
5.权利要求1的呈微囊或植入物形式的组合物，其特征在于所述丙交酯和乙交酯的共聚物由70-80％丙交酯和20-30％乙交酯制得。
6.权利要求1的呈微囊或植入物形式的组合物，其特征在于所述丙交酯和乙交酯的共聚物是L-丙交酯和乙交酯的共聚物。
7.上述权利要求中任一项的微囊或植入物形式的组合物，其特征在于所述蛋白或肽选自：曲普瑞林或其一种盐；兰瑞肽或其一种盐；奥曲肽或其一种盐；具有促黄体生成激素释放激素活性的化合物，曲普瑞林、戈舍瑞林、亮丙瑞林、布舍瑞林及其盐；促黄体生成激素释放激素拮抗剂；糖蛋白IIb/IIIa拮抗剂；具有与糖蛋白IIb/IIIa拮抗剂相似活性的化合物；促红细胞生成素或其类似物；不同类型的干扰素-α、干扰素-β或-γ；生长激素释放抑制因子；生长激素释放抑制因子衍生物；生长激素释放抑制因子类似物；胰岛素；生长激素；生长激素释放因子；生长激素释放肽；表皮生长因子；促黑素细胞素；促甲状腺素释放激素或其盐或其衍生物；甲状腺刺激激素；促黄体素；促滤泡素；甲状旁腺素或其衍生物；溶菌酶盐酸盐；甲状旁腺素相关肽；和人体甲状旁腺激素的N-末端肽片段(1→34位)；后叶加压素或其衍生物；催产素；降钙素；与降钙素具有相似活性的降钙素衍生物；降钙素基因相关肽；高血糖素；高血糖素相似肽；胃泌素；胃泌素释放肽；肠促胰液肽；促胰酶素；缩胆囊素；血管紧张素；人胎盘催乳激素；人绒毛膜促性激素；脑啡肽；脑啡肽衍生物；集落刺激因子；内啡肽；京都酚；白介素类，例如白介素-2；吞噬细胞激素；胸腺生成素；胸腺刺激素；胸腺激素因子；胸腺血清因子；胸腺血清因子衍生物；胸腺素；胸腺因子X；肿瘤坏死因子；胃动素；铃蟾肽或其衍生物；催乳激素；神经降压素；强啡肽；雨蛙肽；P物质；尿激酶；天冬酰胺酶；缓激肽；激肽释放酶；神经生长因子；凝血因子；多粘菌素B；多粘菌素E；短杆菌肽；杆菌肽；蛋白质合成刺激肽；内皮素拮抗剂或其盐或其衍生物；血管活性肠肽；促肾上腺皮质激素或其片段；血小板衍生生长因子；骨形态发生蛋白；垂体腺苷酸环化酶活化多肽；神经肽Y；肽YY；和肠抑胃肽。
8.权利要求7的微囊或植入物形式的组合物，其特征在于所述蛋白或肽选自曲普瑞林乙酸盐、兰瑞肽乙酸盐或奥曲肽乙酸盐。
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| CN107375910B (zh) * | 2017-07-12 | 2020-03-24 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | PTHrP在制备治疗男性性腺功能低下综合征中的应用 |
| CN110547969A (zh) * | 2019-09-03 | 2019-12-10 | 杭州诺泰澳赛诺医药技术开发有限公司 | 一种高比表面积纳米级缓释微粉的生产工艺及设备 |
| IT202000017191A1 (it) | 2020-07-15 | 2022-01-15 | Xbrane Biopharma Ab | Procedimento senza acqua per preparare una composizione farmaceutica per un rilascio più prolungato e controllato di triptorelina o di un suo sale |
| CN112156170B (zh) * | 2020-11-03 | 2022-10-21 | 北京康欣东弘医药科技有限公司 | 可供皮下注射的曲普瑞林缓释微球及其制备方法和用途 |
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| CH661206A5 (fr) | 1983-09-23 | 1987-07-15 | Debiopharm Sa | Procede pour la preparation d'un medicament destine au traitement de maladies hormonodependantes. |
| US4897268A (en) * | 1987-08-03 | 1990-01-30 | Southern Research Institute | Drug delivery system and method of making the same |
| DE3734223A1 (de) * | 1987-10-09 | 1989-04-20 | Boehringer Ingelheim Kg | Implantierbares, biologisch abbaubares wirkstofffreigabesystem |
| US5021554A (en) * | 1989-02-24 | 1991-06-04 | Eli Lilly And Company | Process for protein particle size reduction using a fluid-energy mill |
| GB2246514B (en) | 1990-08-01 | 1993-12-15 | Scras | Sustained release pharmaceutical compositions and the preparation of particles for use therein |
| GB9016885D0 (en) * | 1990-08-01 | 1990-09-12 | Scras | Sustained release pharmaceutical compositions |
| DE4041563A1 (de) * | 1990-12-22 | 1992-06-25 | Sanol Arznei Schwarz Gmbh | Verfahren zur herstellung wirkstoffhaltiger mikropartikel aus hydrolytisch abbaubaren polymeren |
| CH683149A5 (fr) * | 1991-07-22 | 1994-01-31 | Debio Rech Pharma Sa | Procédé pour la préparation de microsphères en matériau polymère biodégradable. |
| DE4223169C1 (de) * | 1992-07-10 | 1993-11-25 | Ferring Arzneimittel Gmbh | Verfahren zur Mikroverkapselung wasserlöslicher Wirkstoffe |
| FR2693905B1 (fr) | 1992-07-27 | 1994-09-02 | Rhone Merieux | Procédé de préparation de microsphères pour la libération prolongée de l'hormone LHRH et ses analogues, microsphères et formulations obtenues. |
| WO1994015587A2 (en) * | 1993-01-06 | 1994-07-21 | Kinerton Limited | Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides |
| US5785976A (en) * | 1993-03-05 | 1998-07-28 | Pharmacia & Upjohn Ab | Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof |
| US6117455A (en) * | 1994-09-30 | 2000-09-12 | Takeda Chemical Industries, Ltd. | Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent |
| ES2237767T3 (es) * | 1995-04-14 | 2005-08-01 | Nektar Therapeutics | Composiciones farmaceuticas en polvo que tienen una dispersabilidad mejorada. |
| CN1102854C (zh) * | 1995-06-07 | 2003-03-12 | 阿尔克姆斯控制治疗公司 | 人生长激素的延续释放组合物 |
| EP0817619A4 (en) * | 1996-01-24 | 1999-02-03 | Us Army | NEW POLY (LACTID / GLYCOLID) MICROSPHERES WITH DELAYED RELEASE WITHOUT INITIAL SHOCK |
| MY118835A (en) * | 1997-04-18 | 2005-01-31 | Ipsen Pharma Biotech | Sustained release compositions and the process for their preparation |
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- 1998-04-17 AT AT98921551T patent/ATE389388T1/de active
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- 1998-04-17 WO PCT/FR1998/000773 patent/WO1998047489A1/fr active IP Right Grant
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